Yohimbin preparations and process of manufacturing same.



' following is a full, 0 ear, and exact speciwith bodies which eliminate the stimulation UNITED STATES PATENT OFFICE.

FRANZ MllLLER, OF WESTEND-OHARLOTTENBURG, GERMANY, ASSIGNOR TO TKEODOR TEICHGRAEBER, OF BERLIN GERMANY.

YOHIMBIN PREPARATIONS AND PROCESS OF MANUFACTURING SAME.

NoIDrawing.

J!" To all whom it may concern:

Be it known that I, FRANZ Murmur, a subject of the German Emperor, and resident of \Vestend-Gharlottenbur in the Kingdom of Prussia, German mpire, have invented new and useful Improvements in Yohimbiu Preparations and in the Processes of Manufacturin Same, of which the fication.

Yohimbin and its salts, which have hitherto been used in medicine exclusively as aphrodisiacs, have the disadvantage that they are sparingly soluble in water and are apt to separate from their solutions; moreover, they stimulate the respiration. The effect of the salts as aphrodisiacs, although desirable in many cases, is injurious when the salts are to be used, in illnesses involving enhanced blood pressure, for the purpose of dilatin the vascular system and thus lowering ie blood pressure. If this effectof yohimbin on the vascular system, which was closely investigated for the first time by myself, is to be applied, it is necessary to find soluble compounds of yohimbin Specification of Letters Patent. Applsaation filed June 24, 1910. Serial No. 568,644.

of the respiration and the sexual organs, without at the same time influencing the at feet of dilatation of the vascular system.

By my invention I make yohimbin preparations having very valuable therapeutic properties in the direction indicated. For this purpose I treat a salt of yohimbin in aqueous, alcoholic or other solution, with at least one molecular proportion of a nitrogen compound which, while neutral in reaction, possesses at the same time basic and acid groups, such as urethanes, aminoacids, acid amids, ureas, or imino compounds with acid groups, like cafl'ein. It is also feasible to arrive at like compounds of yohimbin by treating the free yohimbin base with the salts which the aforesaid neutral compounds formwith acids.

, Although in this specification I have described the products as compounds, I am not sure that they are indeed chemical compounds. This applies especially to those products that are obtained with more than one molecular proportion of the nitrogen compound. The quantity of the latter is va- Patented June 27, 1911.

is not riable within wide limits, provided a and I inferior to one molecular roportion, do not wish to limit myse f to any specified proportion. In the following examples which relate to products containing one or two molecular proportions of the nitrogen compounds, the products are described as compounds for the sake of shortness.

(1 molecular proportion) are dissolved in 1 liter of hot Water together with 9 grams of ethyl urethane (1 molecular proportion) and the solution is' evaporatedin a. vacuum. A yellowish white crystalline powder is thus obtained, melting at 260-261 C. with decomposition and easily soluble without being decomposed in cold and hot water and alcohol of 90 per cent. strength. The compound is insoluble in ether, ligroin, and benzene. By diluted mineral acids it is dissolved without decomposition it carefully heated; from this solution diluted alkalis recipitate the yohimbin base. By cold diluted alkalis the compound is not dissolved and when heated to Example 1: 45 grams of yohimbin nitrate it is decomposed. The composition of the product corresponds to the formula C H sN10a.HNO3.C0(NH- )(ocgll o H mo, being taken as the formula of yohimbin the composition of which is not yet established with absolute certainty.

Example 2: 40 grams of pure yohimbin base (.lf'rnolecular proportion) are suspended in 1 liter of hot water in which the base is almost insoluble, and mixed with 15.5 grams of ethyl urethane nitrate (1 molecular proportion). Solution occurs almost instantaneously. The solution is evaporated in a vacuum, when it yields the same product, melting at 260261 0., as is obtained by the method described in Example 1.

Example 3,: Alpha amino-oxy-iso-hutyric acid is finely powdered and dissolved in boiling water and then mixed with a solution of an equimolecular proportion of yohimbin nitrate'in hot water. The solution is evaporated in a vacuum and finally completely dried over sulfuric acid A yellowish white microcrystalline product is obtained, melting at 260-261 C. with decomposition. It is sparingly soluble. in boiling alcohol of 90 per cent. strength, insoluble in ether, ligroin and benzene, soluble in hot water, in boiling lacial acetic acid and diluted mineral acid. From the latter solution diluted alkalisprecipitate the yohiinbin base. The compound is insoluble in diluted alkalis by which it is decomposed. The composition of the product corresponds to the formula cscnmoauuotcsicwu cmuuncoiu. Example 4: Equimolecular proportions of acetic amid and yohimbin nitrate are dissolved in alcohol of 90 per cent. strength and evaporated to dryness in a vacuum at cnnamoanuorcntconm.

Example 5: Salicylic amid and yohimbin nitrate are dissolved in hot water in equi- .molecular proportions; the solution is filtered and evaporated to dryness in a vacuum. ,Finally the product is completely dried over sulfuric acid. A yellowish white crystalline powder is-obtained, melting with decomposition at about 245 C. It is soluble win .hot water and alcohol of 90 per cent.

strength, insoluble in ether, ligroin and ben- In diluted mineral acids the comzene. pound is soluble without remarkable decom sition when carefully heated. When a-llealis the compound is insoluble and easily addm diluted alkalis' to the solution the yohim in base is precipitated. In diluted decomposed. The composition of the pro uct corresponds rte thai firmula ss notmtoeetmronucomn Exam 1e 6 all uiinolecular proportions of urea an yohiin in nitrate are dissolved in hot-water andthefiltereii solution is evap grated in .a vacuum at low temperature. .55v

,snlfumcaci A nearl Einally the roductl is com letely dried over w iite inicrocrystal- .line powder. is obtains melting at 254255 C.,.W1th,- decomposition. Theproduct is soluhle inihot water, in alcohol of 90 per cent.

strength and in diluted mineral acids. By addin diluted alkalis to the aqueous solution the free yohimbin base is precipitated. The product is insoluble in ether, ligroin and benzene. It is also insoluble in diluted alkalis' by which it is decomposed already at a low temperature. The composition of the product corresponding to the formula CQCISNIIOI-HNOE'CO (NHQL Example 7 Succinic imid and yohimbin nitrate are dissolved in hot water in equimolcculur proportions. The solution is filtered and evaporated to drynessin a vacuum. Finally the productis completely dried over sulfuric acid. Yellowish rliombohedric crystals are obtained, melting at 252-254 C. with decomposition. The product is soluble in hot water and alcohol of 90 per cent. strength, easily soluble in diluted acids from Which solutions diluted alkalis precipitate the yohimbih base. In ether, benzene and Xylol the product is insoluble; it is also insoluble in diluted alkalis. The composition of the product corresponds to the formula Example 8: Equimolecular proportionsof caii'ein and yohimbin nitrate are dissolved in liot water. The solution is filtered and evaporated in a vacuum at as low a temperature as possible. Finally the product is completely dried over sulfuric acid. A yellowish white microcrystalline powder is obtained, melting at 247-249 C. with decomposition. The product is easily soluble in hot water and alcohol of 90 per cent. strength and soluble in diluted acids. From the latter solutions diluted ammonia precipitates the yohinibin base. In diluted alkalis the product is insoluble and is decomposed. The product is also insoluble in ether, benzene and acetone. The composiltion of the product corresponds to the formula Example9: Two molecularproportions of ethyl urethane and one molecular pro ortion of yohimbin nitrate are dissolve in hot water. The solution is filtered and evaporated to dryness in a vacuum at as low a temperature as ossible. The product is thencompletely tried over sulfuric acid. A. yellowish white microcryst-alline powder isobtained," melting at 272275 C. with decomposition. The product is easily soluble in hot water and alcohol of 90 per cent. strength, insoluble in other, ligroin and benzone. In diluted mineral acids it is soluble without decom osit-ion when carefully heat- 'ed. Diluted a alis precipitate the free yohimbin base from this solution. Diluted alkalis do not dissolve the compound which is decomposed when heated therewith.- The composition of the product corresponds to the formula can be substituted for yohim'binhitrate. Of

course, also mixtures of difi'erent yohimbin salts can be used, mixed products being thus obtained.

What I claim is 1. The herein described manufacture of yohimbin preparations soluble in water by bringing together a yohimbin salt with a derivative which, while neutral in reaction, contains both basic and acid groups, one of these two constituents being bound to an acid to form a salt.

2. The herein described manufacture of ohimbin preparations soluble in water by ringing together a yohimbin salt with a nitrogen derivative which, while neutral in reaction, contains both basic and acid groups.

3. The herein described manufacture of ohimbin preparations soluble in water by ringing to ether, in a suitable solvent, yohimbin wit a nitrogen derivative which, while neutral in reaction, contains both basic and acid groups, one of these two constituents being bound to an acid to form a salt, and causing the solvent to evaporate.

4. The herein described manufacture of oh'irnbin preparations soluble in water by ringin together, in a suitable solvent, 'a yohimbin salt with a nitrogen derivative which, while neutral in reaction, contains both basic and acid groups, and causing the solvent to evaporate.

5. The herein described water soluble composition, comprising yohimbin, a nitrogen derivative which, While neutral in reaction, contains both basic and acid groups, and an acid bound to one of said constituents.

6. The herein described Water soluble composition, comprising yohiinbin, a urethane, and an acid bound to one of said constituents.

7. The herein described water soluble composition, comprising yohimbin, ethyl urethane and nitric acid, the latter being bound to one of said constituents, said product forming a yellowish white crystalline powder melting at 260 to 261 1. with decomposition, soluble in water and in alcohol of 90 per cent. strength,insoluble in ether, ligroin and benzene, the composition of said product corresponding to the formula In testimony, that I claim the foregoing as my invention, I have signed my name in presence of two subscribing Witnesses.

. FRANZ MULLER.

W itnesses HENRY HASPER, WoLnnMAn HAUPT. 

